With the favorable prognosis for patients with chronic myeloid leukemia (CML) who completely respond to imatinib (Gleevec(R)) or similar tyrosine-kinase inhibitors (TKIs) like dasatinib and nilotinib, the prevalence of CML is estimated at more than 70,000 patients in the U.S. and is projected to rise to 180,000 by 2050. The current recommendation is to continue therapy indefinitely, but this is at considerable cost to patients and society. TKIs are associated with reduced health status, including fatigue, nausea, depression, sleep disturbances, diarrhea, pain, fluid retention, and skin problems. Moreover, TKI therapies are among the most expensive, costing $92,000-138,000 per patient annually and place a financial burden on the U.S. health care system as well as on individual patients and their families. Small, single-armed studies from Europe and Australia suggest that 22-61% patients with CML in a TKI-induced complete molecular response (MR 4.5) maintain this response after discontinuation of TKIs, and patients whose CML recurred responded to reintroduction of TKI therapy. However, too little is known about the variables governing maintenance of MR 4.5 versus recurrence of CML to recommend TKI discontinuation with monitoring in routine clinical practice. Furthermore the impact of discontinuation on health status and the factors driving a patient's choice have never been studied, leaving patients and providers without guidance. The objective of the proposed Stopping Tyrosine Kinase Inhibitors in CML Patients (Stop TKIs) study is to improve the evidence for decision making regarding TKI discontinuation with monitoring in CML patients in stable MR 4.5. We will pursue 3 specific aims. Aim 1: To characterize the clinical characteristics associated with CML recurrence after TKI discontinuation. We will stop TKI therapy in 170 willing CML patients from 12 cancer centers and closely monitor them for 3 years for recurrence using standard as well as highly sensitive digital blood testing. We will develop a risk-scoring system to predict patients' risk of CML recurrence based on clinical characteristics and recommend an appropriate monitoring schedule for patients who have discontinued TKI therapy. Aim 2: To describe health status changes for patients who discontinue (and restart) TKIs. We will compare patients' reports of their health status while on TKI therapy to their reports of these same outcomes after discontinuation. For patients whose CML recurs, we will describe health status changes after TKI reintroduction. Aim 3: To explore how patients make the decision about TKI discontinue with monitoring. Using qualitative interviews with 20 patients, we will compare patients who are willing to stop TKIs with those who are unwilling to stop. We will evaluate how patients understand and weigh information about TKI discontinuation. The proposed work will be conducted by a multidisciplinary research team supported by a Patient Advisory Panel. At the conclusion of this work, we will have answered critical questions to support patients, physicians, and policy makers considering discontinuation of TKI therapy with monitoring for CML patients.